Sheehy, SH, Duncan, CJ, Elias, SC, Biswas, S, Collins, KA, O’Hara, GA et al.. Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors. PLoS One 7: e31208

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e31208. DOI: 10.1371/journal.pone.0031208
Source: PubMed


Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.
We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4(+)/CD8(+) phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro.
ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection. NCT01095055.

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Available from: Katharine A Collins, Oct 01, 2015
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    • "Adenoviruses isolated from chimpanzees and other great apes group phylogenetically within the human adenovirus species [32] but the seroprevalence of neutralising antibodies against these serotypes in humans is considerably lower than against HAdV-5, prompting the development of chimpanzee adenoviruses (ChAds) as vaccine vectors [8] [42]. ChAd vectors have primed unprecedented frequencies of antigen-specific CD8 + T cells in recent human clinical vaccine trials [26] [35] [36]. "
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    ABSTRACT: Adenovirus vaccine vectors generated from new viral serotypes are routinely screened in pre-clinical laboratory animal models to identify the most immunogenic and efficacious candidates for further evaluation in clinical human and veterinary settings. Here, we show that studies in a laboratory species do not necessarily predict the hierarchy of vector performance in other mammals. In mice, after intramuscular immunization, HAdV-5 (Human adenovirus C) based vectors elicited cellular and humoral adaptive responses of higher magnitudes compared to the chimpanzee adenovirus vectors ChAdOx1 and AdC68 from species Human adenovirus E. After HAdV-5 vaccination, transgene specific IFN-γ(+) CD8(+) T cell responses reached peak magnitude later than after ChAdOx1 and AdC68 vaccination, and exhibited a slower contraction to a memory phenotype. In cattle, cellular and humoral immune responses were at least equivalent, if not higher, in magnitude after ChAdOx1 vaccination compared to HAdV-5. Though we have not tested protective efficacy in a disease model, these findings have important implications for the selection of candidate vectors for further evaluation. We propose that vaccines based on ChAdOx1 or other Human adenovirus E serotypes could be at least as immunogenic as current licensed bovine vaccines based on HAdV-5. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 01/2015; 2(9). DOI:10.1016/j.vaccine.2015.01.042 · 3.62 Impact Factor
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    • "Following vaccination only (dC−1 sera in the Phase IIa trials), there was a highly significant correlation between ELISA responses against recombinant proteins for both alleles of both antigens (Table 2). This was in agreement with previous reported observations from the Phase Ia trials [19], [20] and similar trials of protein-based vaccines [40]. Following CHMI, and exposure to only 3D7 clone parasites, this highly significant correlation was maintained for both antigens in the vaccinated volunteers. "
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    ABSTRACT: The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite - MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors - ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses.
    PLoS ONE 09/2014; 9(9):e107903. DOI:10.1371/journal.pone.0107903 · 3.23 Impact Factor
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    • "As discussed earlier, a Phase I study combining DNA-and/or ChAdV63-prime followed with MVA boost to deliver an HIV- 1 T cell immunogen induced high magnitude T cell responses with potent antiviral capacity (Borthwick et al., 2014). This study and similar studies of malaria vaccines (Sheehy et al., 2011, 2012; O'Hara et al., 2012) showed that the magnitude of T cell responses induced by ChAdV63 alone were modest, but significant boosting was achieved following MVA administration, thus highlighting the superior immunogenic potential of MVA when combined with appropriate priming vectors such as BCG (Whelan et al., 2009; Scriba et al., 2012), natural influenza A virus (Berthoud et al., 2011) or ChAdV63 (Colloca et al., 2012). "
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    ABSTRACT: Development of an effective HIV/AIDS vaccine remains a big challenge, largely due to the enormous HIV diversity which propels immune escape. Thus novel vaccine strategies are targeting multiple variants of conserved antibody and T cell epitopic regions which would incur a huge fitness cost to the virus in the event of mutational escape. Besides immunogen design, the delivery modality is critical for vaccine potency and efficacy, and should be carefully selected in order to not only maximize transgene expression, but to also enhance the immuno-stimulatory potential to activate innate and adaptive immune systems. To date, five HIV vaccine candidates have been evaluated for efficacy and protection from acquisition was only achieved in a small proportion of vaccinees in the RV144 study which used a canarypox vector for delivery. Conversely, in the STEP study (HVTN 502) where human adenovirus serotype 5 (Ad5) was used, strong immune responses were induced but vaccination was more associated with increased risk of HIV acquisition than protection in vaccinees with pre-existing Ad5 immunity. The possibility that pre-existing immunity to a highly promising delivery vector may alter the natural course of HIV to increase acquisition risk is quite worrisome and a huge setback for HIV vaccine development. Thus, HIV vaccine development efforts are now geared toward delivery platforms which attain superior immunogenicity while concurrently limiting potential catastrophic effects likely to arise from pre-existing immunity or vector-related immuno-modulation. However, it still remains unclear whether it is poor immunogenicity of HIV antigens or substandard immunological potency of the safer delivery vectors that has limited the success of HIV vaccines. This article discusses some of the promising delivery vectors to be harnessed for improved HIV vaccine efficacy.
    Frontiers in Microbiology 08/2014; 5:439. DOI:10.3389/fmicb.2014.00439 · 3.99 Impact Factor
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